Smoking tobacco remains the top preventable cause of disease and death in our society. Nicotine withdrawal is a major contributor to the persistent nature of tobacco use, as well as the frequent occurrence of relapse following attempts at smoking cessation. Reduced attentional control is a well-established symptom of nicotine withdrawal. Resumption of smoking/nicotine reduces this attentional disturbance, and may even increase attentional control above baseline levels. Nicotine-induced enhancement of attention may be greater among subgroups that have cognitive-attentional deficits, such as schizophrenia and attention deficit disorder. Importantly, individuals without specific cognitive disorders may possess phenotypes that contribute to the relative degree of attentional disruption during nicotine withdrawal, thereby contributing to the motivation to use tobacco. Individual differences at the molecular genetic level may in part account for these differences. Nicotinic acetylcholine activity is associated with attentional processing, and variants on specific nicotinic acetylcholine receptor genes have been associated with smoking behavior. In addition, nicotine increases dopamine release in many brain areas, including those relevant to attentional control. Indeed, a number of dopamine-related genotypes have been associated with both smoking behavior and attention, albeit in opposing directions. We propose to examine nicotinic-related and dopaminergic genotypes as moderators of nicotine deprivation effects on behavioral and neural indices of attentional control. Two well established tasks (oddball and N-back) will be included to assess attentional control and working memory. These tasks have been studied extensively using event-related brain potential (ERP) methodology. ERP may provide a more sensitive index of cognitive-attentional differences relative to strictly behavioral measures. Eighty-six (43 men) smokers will attend two laboratory sessions following overnight smoking deprivation. In a double-blind and counterbalanced fashion, participants will smoke four nicotine-containing cigarettes throughout one session, and four denicotinized cigarettes during the other. During both sessions, participants will complete the executive attention-related tasks, including concurrent ERP data collection. We hypothesize that the deprived condition will be associated with lower attentional control and working memory, and that genotypes indicative of reduced dopaminergic and nicotinic cholinergic activity will moderate nicotine deprivation induced decrements in attentional control and working memory. We expect to utilize the information gained from this exploratory/developmental research to develop and evaluate smoking cessation and relapse prevention treatment programs. For instance, there are a number of apparently safe and non-addictive nicotine-related compounds believed to improve cognition;these may provide additional support for cessation among smokers with genotypes suggestive of greater vulnerability to withdrawal induced attentional deficits. PUBLIC HEALTH RELEVANCE: The purpose of this research is to better understand disturbances in attentional control resulting from nicotine withdrawal, including genetic moderation of these effects. This research may lead to practical applications, such as matching of individual genetic profiles and cognitive characteristics with appropriate behavioral and pharmacotherapy smoking cessation treatments.